Fungal infections, particularly in immunocompromised patients, are a serious and growing problem. Although antifungal therapeutics have improved greatly, failures and relapse are common. Aspergillus fumigatus is a primary cause of these infections in several patient populations: transplants, leukemics, genetic deficiencies such as chronic granulomatous disease and others, with mortality remaining high. Preventative antifungal vaccines are an attractive, but as yet unrealized, option. The goal of this proposal is to develop a prototype glucan-protein vaccine by conjugating a protein to a particulate ?-glucan immunomodulator (i.e., WGP), a cell wall component of many pathogenic fungi. Preliminary work using WGP alone or conjugated to a non-specific protein, bovine serum albumin (BSA), indicated that a glucan-protein vaccine was active against Aspergillus and Coccidioides. The work described in this proposal will examine the potential of conjugating a specific, immunodominant recombinant protein from Aspergillus (i.e., Aspf3) to WGP and enhancing the protective capacity of the vaccine in comparison to a conjugate with a non-fungal protein, BSA. Preliminary studies demonstrated that such a glucan-protein vaccine would also have the potential to be cross-protective against other fungi;thus, in addition to testing against Aspergillus, the vaccine preparations will be tested against Coccidioides, a serious primary fungal pathogen in normal or immunosuppressed individuals, considered an emerging Category C pathogen by NIH. The hope is to demonstrate maximum cross protection, which would provide the basis for development of this glucan-protein conjugate vaccine as a model panfungal vaccine that is both safe and effective against serious fungal infections caused by diverse fungi. To further the understanding of what part of the immune response is critical to the induction of protective immunity in these systems, cytokine and antibody profiles induced by protective vaccines and less-protective or non-protective preparations will be studied, with a goal of determining a set of surrogate markers indicative that a vaccine would be protective. The most productive route to a fungal vaccine is a conjugate vaccine that combines an optimally configured glucan with a specific immunogenic protein. The rationale for this proposal comes from work to date, which suggests that some proteins may be sufficiently cross-immunogenic that when combined with the appropriate cross-immunogenic glucan it may be possible to develop a pan-fungal vaccine. The studies proposed in this Phase I application have the potential of leading to future production and commercialization of a much desired panfungal vaccine. A vaccine of this type would not only save significant healthcare costs, but would reduce serious fungal infection in numerous patients and more importantly, save lives.
An immunomodulatory yeast-derived beta glucan as a component of a conjugate pan-fungal vaccine Based on our preliminary work showing the possibility of developing a conjugate panfungal vaccine, we will develop a vaccine initially directed against Aspergillus fumigatus, the second most common cause of nosocomial, invasive fungal infections in the US and most lethal such infection in immune-compromised patients. For this: 1, we will study an immunomodulatory glucan-protein conjugate, as a vaccine;2, identify whether conjugation of a specific Aspergillus protein to the glucan is superior to glucan alone or conjugated to a non-fungal protein;3, test the vaccine against another fungus, Coccidioides (lethal even in non-immunocompromised persons), in a proof of principle test toward the goal of developing a panfungal vaccine;and finally, 4, examine the immunological profiles of protective vs. less protective and non-protective preparations to predict and better understand the nature of the protective immune response. In summary, the development of a safe and effective pan-fungal vaccine will have a significant impact in reducing healthcare expenditures, by reducing serious infections requiring long-term and possibly life-long therapy, and most importantly, save lives, as well as reducing the threat of a potential agent of biowarfare (Coccidioides) against military personnel and civilians.
